Method for dehydrating organic compounds in a microreactor

ABSTRACT

The present invention relates to a process for the dehydration of organic compounds to give unsaturated compounds.

The present invention relates to a process for the dehydration oforganic compounds to give unsaturated compounds.

The dehydration of suitable organic compounds to give unsaturatedcompounds is a process which is carried out very frequently in thechemical industry and whose considerable importance is also reflected innumerous publications on this subject.

However, the performance of dehydrations of this type on an industrialscale is accompanied by safety problems and dangers. Firstly, use isfrequently made of relatively large amounts of highly toxic chemicalsubstances, which in themselves already represent a considerable risk topeople and the environment, and secondly the reaction conditions can inmany cases only be controlled well with considerable effort.

The object of the present invention is therefore to provide a processfor the dehydration of organic compounds to give unsaturated compoundswhich avoids the above-mentioned disadvantages. In particular, It shouldbe possible to carry out this process in a simple, reproducible mannerwith increased safety for humans and the environment and with goodyields, and the reaction conditions should be very easy to control.

This object is achieved, surprisingly, by the process according to theinvention for the dehydration of organic compounds to give unsaturatedcompounds, in which at least one organic compound in liquid or dissolvedform is mixed with at least one dehydrating agent in liquid or dissolvedform in at least one microreactor and reacted for a residence time, andthe dehydrated compound is, if desired, isolated from the reactionmixture.

Advantage embodiments of the process according to the invention aredescribed in the sub-claims.

In accordance with the invention, individual organic compounds ormixtures of at least two of these compounds can be dehydrated by theclaimed process. Preferably, individual organic compounds are employedin the process according to the invention.

For the purposes of the invention, a microreactor is a reactor having avolume of ≦1000 μl in which the liquids and/or solutions are intimatelymixed at least once. The volume of the microreactor is preferably ≦100μl, particularly preferably ≦50 μl.

The microreactor is preferably made from thin silicon structuresconnected to one another.

The microreactor is preferably a miniaturised flow reactor, particularlypreferably a static micromixer. The microreactor is very particularlypreferably a static micromixer as described in the patent applicationhaving the international publication number WO 96/30113, which isincorporated herein by way of reference and is regarded as part of thedisclosure.

A microreactor of this type has small channels in which liquids and/orchemical compounds in the form of solutions are mixed with one anotherby means of the kinetic energy of the flowing liquids and/or solutions.

The channels of the microreactor preferably have a diameter of from 10to 1000 μm, particularly preferably from 20 to 800 μm and veryparticularly preferably from 30 to 400 μm.

The liquids and/or solutions are preferably pumped into the microreactorin such a way that they flow through the latter at a flow rate of from0.01 μl/min to 100 ml/min, particularly preferably from 1 μl/min to 1ml/min.

In accordance with the invention, the microreactor is preferablyheatable.

In accordance with the invention, the microreactor is preferablyconnected via an outlet to at least one residence zone, preferably acapillary, very particularly preferably a heatable capillary. Aftermixing in the microreactor, the liquids and/or solutions are fed intothis residence zone or capillary in order to extend their residencetime.

For the purposes of the invention, the residence time is the timebetween mixing of the starting materials and work-up of the resultantreaction solution for analysis or isolation of the desired product(s).

The residence time necessary in the process according to the inventiondepends on various parameters, such as, for example, the temperature orreactivity of the starting materials. It is possible for the personskilled in the art to match the residence time to these parameters andthus to achieve an optimum course of the reaction.

The residence time of the reaction solution in the system usedcomprising at least one microreactor and, if desired, a residence zonecan be adjusted through the choice of the flow rate of the liquidsand/or solutions employed.

The reaction mixture is likewise preferably passed through two or moremicroreactors connected in series. This achieves an extension of theresidence time, even at an increased flow rate, and the dehydrationreaction components employed are reacted in such a way that an optimumproduct yield of the desired dehydrated unsaturated compound(s) isachieved.

In a further preferred embodiment, the reaction mixture is passedthrough two or more microreactors arranged in parallel in order toincrease the throughput.

In another preferred embodiment of the process according to theinvention, the number and arrangement of the channels in one or moremicroreactor(s) are varied in such a way that the residence time isextended, likewise resulting in an optimum yield of the desireddehydrated unsaturated compound(s) at the same time as an increased flowrate.

The residence time of the reaction solution in the microreactor, whereappropriate in the microreactor and the residence zone, is preferably≦15 hours, particularly preferably ≦3 hours, very particularlypreferably ≦1 hour.

The process according to the invention can be carried out in a verybroad temperature range, which is essentially restricted by the heatresistance of the materials employed for the construction of themicroreactor, any residence zone and further constituents, such as, forexample, connections and seals, and by the physical properties of thesolutions and/or liquids employed. The process according to theinvention is preferably carried out at a temperature of from −100 to+250° C., particularly preferably from −78 to +150° C., veryparticularly preferably from 0 to +40° C.

The process according to the invention can be carried out eithercontinuously or batchwise. It is preferably carried out continuously.

For carrying out the process according to the invention for thedehydration of organic compounds to give unsaturated compounds, it isnecessary that the dehydration reaction be carried out as far aspossible in the homogeneous liquid phase containing no or only verysmall solid particles since otherwise the channels present in themicroreactors become blocked.

The course of the dehydration reaction in the process according to theinvention can be followed using various analytical methods known to theperson skilled in the art and regulated if necessary. The course of thereaction is preferably followed by chromatography, particularlypreferably by gas chromatography, for example by GC-MS, and/or byhigh-pressure liquid chromatography and regulated if necessary.

The course of the reaction is very particularly preferably followed byhigh-pressure liquid chromatography. Control of the reaction in theprocess according to the invention is significantly improved comparedwith known processes.

After the reaction, the dehydrated products are isolated if desired. Thedehydrated product(s) is (are) preferably isolated from the reactionmixture by extraction.

Organic compounds which can be employed in the process according to theinvention are all organic compounds which are known to the personskilled in the art as substrates for dehydrations and which dehydratewith formation of unsaturated compounds. The organic compounds arepreferably selected from aliphatic, aromatic or heteroaromatic alcohols,amides or aldoximes.

For the purposes of the invention, “unsaturated compounds” means thatthe dehydration results in the formation of an unsaturated organiccompound or an increase in the unsaturated character of the compound ifthe compound is already unsaturated. This thus includes the dehydrationof alcohols to give alkenes and of amides or aldoximes to give nitrites.

Aliphatic alcohols, amides or aldoximes which can be employed are allaliphatic compounds from the above-mentioned classes of substance whichare known to the person skilled in the art and which are suitable assubstrate for dehydrations in which unsaturated compounds are formed.This also includes straight-chain, branched, saturated or unsaturatedcompounds.

Aromatic alcohols, amides or aldoximes which can be employed are allaromatic compounds from the above-mentioned classes of substance whichare known to the person skilled in the art and which are suitable assubstrate for dehydrations in which unsaturated compounds are formed.For the purposes of the invention, this thus includes compounds and/orderivatives which have a monocyclic and/or polycyclic homoaromatic basicstructure or a corresponding moiety, for example in the form ofsubstituents.

Heteroaromatic alcohols, amides or aldoximes which can be employed areall heteroaromatic compounds from the above-mentioned classes ofsubstance which are known to the person skilled in the art and which aresuitable as substrate for dehydrations in which unsaturated compoundsare formed and which contain at least one hetero atom. For the purposesof the invention, heteroaromatic compounds include heteroaromaticcompounds and/or derivatives thereof which have at least one monocyclicand/or polycyclic heteroaromatic basic structure or a correspondingmoiety, for example in the form of substituents. Heteroaromatic basicstructures or moieties preferably contain at least one oxygen, nitrogenor sulfur atom.

Dehydrating agents which can be employed in the process according to theinvention are all dehydrating agents which are known to the personskilled in the art and which are suitable for the dehydration of organiccompounds to give unsaturated compounds, or mixtures of at least twocomponents. Preferably, a single dehydrating agent is employed in eachcase in the process according to the invention.

In a further preferred embodiment, the dehydrating agent is at least onecompound selected from acids, acid anhydrides, acid halides,carbodiimides or cyanoformates, or a mixture of these dehydratingagents. The acid used is preferably p-toluenesulfonic acid,methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochloricacid, perchloric acid, or a mixture of two or more of these acids.Preferred acid anhydrides are acetic anhydride, trifluoroaceticanhydride, trifluoromethanesulfonic anhydride, or a mixture thereof.Chlorosulfonic acid, chlorosulfonyl isocyanate, acetyl chloride,trichloroacetyl chloride, p-toluenesulfonyl chloride, methanesulfonylchloride, phosgene, diphosgene, triphosgene, phosphorus oxychloride,phosphorus trichloride, phosphorus tribromide,hexachlorocyclophosphatriazine, thionyl chloride, and mixtures thereofare preferred acid halides. Furthermore, ethyl cyanoformate is apreferred cyanoformate. Examples of preferred carbodiimides includedicyclohexylcarbodiimide, carbonyldiimidazole, and mixtures thereof.

In the process according to the invention, the molar ratio of organiccompound employed to dehydrating agent employed depends on thereactivity of the organic compounds employed and the dehydrating agents.The dehydrating agent and the organic compound are preferably used in anequimolar ratio. In a further preferred embodiment, the dehydratingagent is employed in a 1.3-fold to 10-fold molar excess relative to theorganic compound, particularly preferably in a 3-fold to 6-fold excess,very particularly preferably in a 4-fold to 5-fold excess.

The selectivity of the reaction depends, besides on the concentration ofthe reagents employed, on a number of further parameters, such as, forexample, the temperature, the type of dehydrating agent used or theresidence time. It is possible for the person skilled in the art tomatch the various parameters to the respective dehydration reaction insuch a way that the desired dehydrated product(s) is (are) obtained.

It is essential for the process according to the invention that theorganic compounds and dehydrating agent employed are either themselvesliquid or are in dissolved form. If these compounds are not themselvesalready in liquid form, they must therefore be dissolved in a suitablesolvent before the process according to the invention is carried out.Preferred solvents are halogenated solvents, particularly preferablydichloromethane, chloroform, 1,2-dichloroethane or1,1,2,2-tetrachloroethane, straight-chain, branched or cyclic paraffins,particularly preferably pentane, hexane, heptane, octane, cyclopentane,cycloheptane or cyclooctane, or straight-chain, branched or cyclicethers, particularly preferably diethyl ether, methyl tert-butyl ether,tetrahydrofuran or dioxane, aromatic solvents, particularly preferablytoluene, xylenes, ligroin or phenyl ether, N-containing heterocyclicsolvents, particularly preferably N-methylpyrrolidone, or mixtures ofthese solvents.

In the process according to the invention, the danger to people and theenvironment due to released chemicals is considerably reduced and thusresults in increased safety during handling of hazardous materials. Thedehydration of organic compounds by the process according to theinvention furthermore enables better control of the reaction conditions,such as, for example, reaction duration and reaction temperature, thanis possible in the conventional processes. The temperature can beselected individually and kept constant in each volume unit of thesystem. The course of the dehydration reaction in the reduction can beregulated very quickly and precisely in the process according to theinvention. The dehydrated unsaturated products can thus be obtained invery good and reproducible yields.

It is also particularly advantageous that the process according to theinvention can be carried out continuously. This makes it faster and lessexpensive compared with conventional processes, and it is possible toprepare any desired amounts of the dehydrated unsaturated compoundswithout major measurement and control effort.

The invention is explained below with reference to an example. Thisexample serves merely to explain the invention and does not restrict thegeneral inventive idea.

EXAMPLES

Dehydration of Benzaldoxime to Benzonitrile

The dehydration of benzaldoxime using methanesulfonyl chloride wascarried out in a static micromixer (Technical University of Ilmenau,Faculty of Machine Construction, Dr.-Ing. Norbert Schwesinger, PO Box100565, D-98684, Ilmenau) having a physical size of 40 mm×25 mm×1 mm andhaving a total of 11 mixing stages with a volume of 0.125 μl each. Thetotal pressure loss was about 1000 Pa.

The static micromixer was connected via an outlet and an Omnifitmedium-pressure HPLC connector (Omnifit, Great Britain) to a Tefloncapillary having an internal diameter of 0.49 mm and a length of 1.0 m.The reaction was carried out at room temperature.

A 2 ml disposable injection syringe was filled with part of a solutionof 1.0 g (8 mmol) of benzaldoxime and 8 ml of N-methylpyrrolidone, and afurther 2 ml syringe was filled with part of a solution of 1.4 g (12mmol) of methanesulfonyl chloride in 8 ml of N-methylpyrrolidone. Thecontents of the two syringes were subsequently transferred into thestatic micromixer by means of a metering pump (Harvard Apparatus Inc.,Pump 22, South Natick, Mass., USA). Before performance of the reaction,the experimental arrangement was calibrated with respect to thedependence of the residence time on the pump flow rate. The residencetime was set to 3.75 minutes. The reactions were followed with the aidof a Merck Hitachi LaChrom HPLC instrument. The temperature of thestatic micromixer and the Teflon capillary were controlled in a jacketedvessel thermostatted at 150° C.

For a reaction duration of 3.75 minutes, complete conversion of thebenzaldoxime exclusively into benzonitrile was observed.

1. A process for dehydration of an organic compound to obtain thecorresponding unsaturated compound said process comprising: mixing atleast one organic compound in liquid or dissolved form with at least onedehydrating reagent in liquid or dissolved form in at least onemicroreactor, and reacting said at least one organic compound and saidat least one dehydrating reagent therein for a sufficient time to obtainthe corresponding unsaturated compound, and optionally isolating thecorresponding unsaturated compound from the reaction mixture, whereinsaid at least one organic compounds is selected from aliphatic alcohols,aromatic alcohols, heteroaromatic alcohols, aliphatic amides, aromaticamides, heteroaromatic amides, aliphatic aldoximes, aromatic aldoximes,and heteroaromatic aldoximes, and said at least one dehydrating agent isselected from acids, acid anhydrides, acid halides, carbodiimides andcyanoformates.
 2. A process according to claim 1, wherein themicroreactor is a miniaturized flow reactor.
 3. A process according toclaim 1, wherein the microreactor is a static micromixer.
 4. A processaccording to claim 1, wherein the microreactor is connected via anoutlet to a capillary.
 5. A process according to claim 1, wherein thevolume of the microreactor is ≦100 μl.
 6. A process according to claim1, wherein the microreactor is heatable.
 7. A process according to claim1, wherein the microreactor has channels which have a diameter of from10 to 1000 μm.
 8. A process according to claim 1, wherein the reactionmixture flows through the microreactor at a flow rate of from 0.01μl/min to 100 ml/min.
 9. A process according to claim 1, wherein theresidence time of the compounds employed in the microreactor is ≦15hours.
 10. A process according to claim 1, wherein said process iscarried out at a temperature of from −100 to +250° C., preferably from−78 to +150° C., particularly preferably from 0 to +40° C.
 11. A processaccording to claim 1, the course of the reaction is followed bychromatography and optionally regulated.
 12. A process according toclaim 1, wherein said at least one dehydrating agent is an acid selectedfrom p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid,sulfuric acid, hydrochloric acid, perchloric acid, and mixtures thereof.13. A process according to claim 1, wherein said at least onedehydrating agent is an acid anhydride selected from acetic anhydride,trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, andmixtures thereof.
 14. A process according to claim 1, wherein said atleast one dehydrating agent is an acid halide selected fromchlorosulfonic acid, chlorosulfonyl isocyanate, acetyl chloride,trichloroacetyl chloride, p-toluenesulfonyl chloride, methanesulfonylchloride, phosgene, diphosgene, triphosgene, phosphorus oxychloride,phosphorus trichloride, phosphorus tribromide,hexachlorocyclophosphatriazine, thionyl chloride, and mixtures thereof.15. A process according to claim 1, wherein said at least onedehydrating agent is ethyl cyanoformate.
 16. A process according toclaim 1, wherein said at least one dehydrating agent is a carbodiimideselected from dicyclohexylcarbodiimide, carbonyldiimidazole, andmixtures thereof.
 17. A process according to claim 1, wherein thedehydrating agent is employed in an equimolar ratio.
 18. A processaccording to claim 4, wherein the capillary is a heatable capillary. 19.A process according to claim 5, wherein the volume of the microreactoris ≦50 μl.
 20. A process according to claim 7, wherein said channelshave a diameter of from 20 to 800 μm.
 21. A process according to claim20, wherein said channels have a diameter of from 30 to 400 μm.
 22. Aprocess according to claim 8, wherein the reaction mixture flows throughthe microreactor at a flow rate of from 1 μl/min to 1 ml/min.
 23. Aprocess according to claim 9, wherein the residence time of thecompounds employed in the microreactor is ≦1 hour.
 24. A processaccording to claim 10, wherein said process is carried out at atemperature of from −78 to +150° C.
 25. A process according to claim 24,wherein said process is carried out at a temperature of from 0 to +40°C.
 26. A process according to claim 1, wherein the dehydrating agent isemployed in a 1.3-fold to 10-fold molar excess relative to the organiccompound.
 27. A process according to claim 26, wherein the dehydratingagent is employed in a 3-fold to 6-fold molar excess relative to theorganic compound.
 28. A process according to claim 27, wherein thedehydrating agent is employed in a 4-fold to 5-fold molar excessrelative to the organic compound.
 29. A process according to claim 1,wherein said at least one dehydrating agent is selected fromp-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid,sulfuric acid, hydrochloric acid, perchloric acid, acetic anhydride,trifluoroacetic anhydride, trifluoromethanesulfonic anhydride,chlorosulfonic acid, chlorosulfonyl isocyanate, acetyl chloride,trichloroacetyl chloride, p-toluenesulfonyl chloride, methanesulfonylchloride, phosgene, diphosgene, triphosgene, phosphorus oxychloride,phosphorus trichloride, phosphorus tribromide,hexachlorocyclophosphatriazine, thionyl chloride, ethyl cyanoformate,dicyclo-hexylcarbodiimide, and carbonyldiimidazole.
 30. A processaccording to claim 1, wherein said at least one organic compound andsaid at least one dehydrating agent are dissolved in a solvent selectedfrom halogenated solvents, straight-chain paraffins, branched paraffins,cyclic paraffins, straight-chain ethers, branched ethers, cyclic ethers,aromatic solvents, N-containing heterocyclic solvents, or mixturesthereof.
 31. A process according to claim 30, wherein said at least oneorganic compound and said at least one dehydrating agent are dissolvedin a solvent selected from dichloromethane, chloroform,1,2-dichloroethane, 1,1,2,2-tetra-chloroethane, pentane, hexane,heptane, octane, cyclopentane, cycloheptane, cyclooctane, diethyl ether,methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylenes,ligroin, phenyl ether, N-methylpyrrolidone, or mixtures thereof.
 32. Aprocess according to claim 29, wherein said at least one organiccompound and said at least one dehydrating agent are dissolved in asolvent selected from halogenated solvents, straight-chain paraffins,branched paraffins, cyclic paraffins, straight-chain ethers, branchedethers, cyclic ethers, aromatic solvents, N-containing heterocyclicsolvents, or mixtures thereof.
 33. A process according to claim 32,wherein said at least one organic compound and said at least onedehydrating agent are dissolved in a solvent selected fromdichloromethane, chloroform, 1,2-dichloroethane,1,1,2,2-tetra-chloroethane, pentane, hexane, heptane, octane,cyclopentane, cycloheptane, cyclooctane, diethyl ether, methyltert-butyl ether, tetrahydrofuran, dioxane, toluene, xylenes, ligroin,phenyl ether, N-methylpyrrolidone, or mixtures thereof.
 34. A processaccording to claim 1, wherein said at least one organic compound isbenzaldoxime and said at least one dehydrating agent is methanesulfonylchloride.